There is compelling evidence that malignant melanoma cells evoke specific humoral and cellular anti-tumor immune responses in some patients. For example, the radial growth phase of primary melanoma is regularly associated with a significant dermal lymphocytic reaction that often results in partial tumor destruction. Moreover, clonal expansion of T cells occurs in primary regressing melanoma; lymphocytes explanted from such lesions demonstrate cytotoxicity towards autologous melanoma cells in vitro.
Although a brisk lymphocytic infiltrate in the vertical growth phase of primary melanoma occurs infrequently, this response is tightly correlated with prolonged survival and a reduced incidence of metastatic disease. Melanoma that has spread to regional lymph nodes may occasionally elicit a striking lymphocytic reaction which is also highly associated with improved survival. In rare cases, widely disseminated melanoma may undergo spontaneous regression accompanied by a diffuse infiltrate of lymphocytes, plasma cells, and macrophages. Notwithstanding these provocative findings, however, it is clear that most patients fail to develop anti-melanoma immune responses that are sufficiently potent to prevent lethal tumor progression.
The application of gene transfer technologies to investigative efforts in tumor immunology has led to the development of several novel strategies to enhance the frequency and intensity of anti-tumor immune responses. A large number of pre-clinical studies have convincingly demonstrated that engineering murine tumor cells to express a variety of immunostimulatory molecules can lead to enhanced tumor immunogenicity. Among the approaches utilizing ex vivo modification of tumor cells, we have shown that vaccination with irradiated tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF) stimulates potent, specific, and long-lasting anti-tumor immunity in multiple murine tumor model systems, including malignant melanoma (Dranoff et al., Proc. Natl. Acad. Sci., U.S.A., 90:3539-3543, 1993). Immunization requires the participation of both CD4- and CD8-positive T lymphocytes and likely involves improved tumor antigen presentation by dendritic cells and macrophages recruited to the vaccination site. Identification of individual tumor antigens is likely to contribute to improved cancer diagnosis and treatment.